Synthesis and biological evaluation of 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives, a novel group of anticancer agents active on a multidrug resistant cell line

被引:49
作者
Stefanska, B
Arciemiuk, M
Bontemps-Gracz, MM
Dzieduszycka, M
Kupiec, A
Martelli, S
Borowski, E [1 ]
机构
[1] Gdansk Tech Univ, Dept Pharmaceut Technol & Biochem, PL-80952 Gdansk, Poland
[2] Univ Camerino, Dept Chem, I-62033 Camerino, Italy
关键词
D O I
10.1016/S0968-0896(02)00425-X
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[tic,h]cinnoline-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a-e), or 6 (2a-f) or disubstituted at positions 2 and 6 (4a-c) or 2 and 8 (17a-e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L 12 10) and human leukemia (K562) cell lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) cell line with resistance index (RI) in the range 1-3 depending on the compound's structure. Two of the most active in vitro compounds 4a and 11 were tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone. DNA-binding assays were performed and DNA affinity data were correlated with the structures of the compounds. The cytoplasmatic membrane affinity values (log k'(IAM)) have also been determined and the correlation with the resistance indexes discussed. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance. (C) 2002 Elsevier Science Ltd. All rights reserved.
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页码:561 / 572
页数:12
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